Megan Spence

Our research focuses on peripheral and integral membrane proteins with nuclear magnetic resonance (NMR); techniques.  Although one third of eukaryotic proteins are membrane proteins, only a handful have been structurally characterized, putting membrane-associated proteins at the frontier of structural biology. The partly-ordered nature of these membrane-associated systems requires us to develop new NMR techniques for systems at the solids / liquids interface as well as employing existing solid-state and solution-state NMR techniques.

 

Questions we can ask about these proteins / membrane systems include:

 

What is the structure of the protein on the membrane?

What is the orientation of the protein with respect to the membrane?

What are the dynamics of the protein on the membrane?

How does the protein affect the membrane structure and dynamics?

 

We are particularly interested in a group of neurotoxins isolated from tarantula venom whose mechanism of toxicity involves inhibiting transmembrane ion channels.  Recent work by Lee and MacKinnon¹ has shown that the neurotoxin, a small water-soluble protein, actually dissolves in the hydrophobic lipid bilayer and may affect the ion channel indirectly, via a lipid-mediated mechanism.² Confirmation of this hypothesis would demonstrate an entirely novel mechanism of protein-protein interaction.  NMR structural studies of the toxins in the membrane, as well as solid-state NMR studies of the membrane itself, could offer insight to the molecular mechanism of this ion channel inhibition.

 

1 Lee, S.Y. and R. MacKinnon, A membrane-access mechanism of ion channel inhibition by voltage sensor toxins from spider venom. Nature, 2004. 430(6996);: p. 232-235.

 

2 Suchyna, T.M., et al., Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers. Nature, 2004. 430(6996);: p. 235-240.